Liquid and low melting coatings for stents

ABSTRACT

Stents with coatings comprising a combination of a restenosis inhibitor comprising an HMG-CoA reductase inhibitor and a carrier. Also provided are methods of coating stents with a combination of an HMG-CoA reductase inhibitor and a carrier. A preferred example of a restenosis inhibitor is cerivastatin. The stent coatings have been shown to release restenosis inhibitors in their active forms.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/891,953, filed Sep. 28, 2010, which is a continuation of U.S. patentapplication Ser. No. 11/959,889, filed Dec. 19, 2007, now U.S. Pat. No.7,829,111, which is a continuation of U.S. patent application Ser. No.10/027,374 filed Dec. 21, 2001, now U.S. Pat. No. 7,323,189, which is acontinuation-in-part of U.S. patent application Ser. No. 09/991,235,filed Oct. 22, 2001, now abandoned, the disclosures of which areincorporated herein by reference in their entirety.

BACKGROUND

1. Field of the Invention

The present invention generally relates to stent coatings that includebioactive compounds that inhibit restenosis.

2. Description of the Related Art

Stents are often used in the treatment of atherosclerosis, a disease ofthe vascular system in which arteries become partially, and sometimescompletely, occluded with substances that may include lipids,cholesterol, calcium, and various types of cells, such as smooth musclecells and platelets. Atherosclerosis is a very common disease that canbe fatal, and methods of preventing the accumulation of occludingcompounds in arteries are being investigated.

Percutaneous transluminal angioplasty (PTA) is a commonly used procedureto break up and/or remove already formed deposits along arterial walls.PTA can also be used to treat vascular occlusions not associated withatherosclerosis. During PTA, a catheter is threaded through a patient'sarteries until the occluded area to be treated is reached. A balloonattached to the end of the catheter is then inflated at the occludedsite. The expanded balloon breaks up the mass of occluding substances,resulting in a more open arterial lumen. However, there is a risk thatthe artery may re-close within a period of from one day to approximatelysix months of the procedure. This re-closure is known as restenosis.Accordingly, a balloon-only angioplasty procedure often does not resultin a permanently reopened artery. To prevent restenosis, scaffoldingdevices called stents are deployed in the lumen of the artery as astructural support to maintain the lumen in an open state. Unlike theballoon and the catheter used in an angioplasty procedure, the stentusually remains in the artery as a permanent prosthesis. Althoughtechnically feasible, removal of the stent from the artery is generallyavoided.

Stents are typically elongated structures used to keep open lumens(e.g., openings in the body) found in various parts of the body so thatthe parts of the body containing those lumens may function properly.Stents are usually implanted at their site of use in the body byattaching them in a compressed state to a catheter that is directedthrough the body to the site of stent use. The stent can be expanded toa size which enables it to keep the lumen open by supporting the wallsof the lumen once it is positioned at the desired site.

The lumens of blood vessels are common sites of stent deployment.Vascular stents are frequently used in blood vessels to open the vesseland provide improved blood flow. The stents are typically hollow,cylindrical structures made from struts or interconnected filaments.Vascular stents can be collapsed to reduce their diameter so that thestent can be guided through a patients arteries or veins to reach thesite of deployment. Stents are typically either coupled to the outsideof the balloon for expansion by the expanding balloon or areself-expanding upon removal of a restraint such as a wire or sleevemaintaining the stent in its collapsed state.

The stent is allowed to expand at the desired site to a diameter largeenough to keep the blood vessel open. Vascular stents are often made ofmetal to provide the strength necessary to support the occluded arterialwalls. Two of the preferred metals are Nitinol alloys of nickel andtitanium, and stainless steel. Other materials that can be used infabricating stents are ceramics, polymers, and plastics. Stents may becoated with a substance, such as a biodegradable or biostable polymer,to improve the biocompatibility of the stent, making it less likely tocause an allergic or other immunological response in a patient. Acoating substance may also add to the strength of the stent. Some knowncoating substances include organic acids, their derivatives, andsynthetic polymers that are either biodegradable or biostable. Biostablecoating substances do not degrade in the body, biodegradable coatingsubstances can degrade in the body. A problem with known biodegradableand biostable stent coatings is that both types of coatings aresusceptible to breaking and cracking during the temperature changes andexpansion/contraction cycles experienced during stent formation and use.

Stents located within any lumen in the body may not always preventpartial or complete restenosis. In particular, stents do not alwaysprevent the re-narrowing of an artery following PTA. In fact, theintroduction and presence of the stent itself in the artery or vein cancreate regions of trauma such as, e.g., tears in the inner lining of theartery, called the endothelium. It is believed that such trauma cantrigger migration of vascular smooth muscle cells, which are usuallyseparated from the arterial lumen by the endothelium, into the arteriallumen, where they proliferate to create a mass of cells that may, in amatter of days or weeks, occlude the artery. Such re-occlusion, which issometimes seen after PTA, is an example of restenosis. Coating a stentwith a substance to make the surface of the stent smoother and tominimize damage to the endothelium has been one method used to createstents that are less likely to contribute to restenosis.

Currently, drug therapy for restenosis primarily consists of thesystemic administration of drugs. However, delivering drugs in thismanner may result in undesirable side effects in other areas of the bodyunrelated to the vascular occlusion. Also, the administered dose of adrug that is delivered systemically is less effective in achieving thedesired effect in the local area of the body in which it is needed. Forexample, an anti-restenosis drug delivered systemically may besequestered or metabolized by other parts of the body, resulting in onlya small amount of the drug reaching the local area in which it isneeded.

Stents with bioactive compounds or drugs in or on their coatings can beused. One class of drugs that can be used in stent coatings isrestenosis inhibitors. There remains a need for coatings that can beshown to actually release the restenosis inhibiting compounds in theiractive forms. Further, there is a need for stents that can carry drugsand release them in a sufficient concentration to produce the desiredeffect. In particular, there is a need for such stents that can inhibitrestenosis.

SUMMARY OF INVENTION

Broadly, the invention relates to coated stents, methods of makingcoated stents and methods of using coated stents. In one aspect, theinvention can include a coated stent comprising a stent and a coatingcomprising a substantially unreacted HMG-CoA reductase inhibitor. It ispreferred that the coating also comprise a carrier for the HMG-CoAreductase inhibitor. In a specific embodiment, the HMG-CoA reductaseinhibitor is provided in a nonpolymeric carrier. In another embodiment,the HMG-CoA reductase inhibitor is provided in a polymeric carrier,which may be physically bound to the polymer, chemically bound to thepolymer, or both. The coating composition can be a liquid solution atroom and/or body temperature, which may include the HMG-CoA reductaseinhibitor and the polymeric or nonpolymeric carrier, and which mayadditionally include a solvent which later may be removed, e.g., bydrying. Alternatively, the coating composition may be a solid at roomand body temperature.

The coating composition preferably includes an effective amount of theHMG-CoA reductase inhibitor. More particularly, the coating compositionpreferably includes an amount of the HMG-CoA reductase inhibitor that issufficient to be therapeutically effective for inhibiting regrowth ofplaque or inhibiting restenosis. In one embodiment, the coatingcomposition may include from about 1 wt % to about 50 wt % HMG-CoAreductase inhibitor, based on the total weight of the coatingcomposition. In another embodiment, the coating composition includesfrom about 5 wt % to about 30 wt % HMG-CoA reductase inhibitor. In yetanother embodiment, the coating composition includes from about 10 wt %to about 20 wt % HMG-CoA reductase inhibitor. Any HMG-CoA reductaseinhibitor may be used, but the HMG-CoA reductase inhibitor is preferablyselected from the group consisting of cerivastatin, atorvastatin,simvastatin, fluvastatin, lovastatin, and pravastatin. More preferably,the HMG-CoA reductase inhibitor is cerivastatin. In another embodiment,the coating composition comprises more than one HMG-CoA reductaseinhibitor. In another embodiment, the coating composition includes arestenosis inhibitor that is not an HMG-CoA reductase inhibitor.

In one embodiment, the coating composition comprises an effective amountof a polymeric carrier, e.g., an amount sufficient to provide a polymermatrix or support for the inhibitor. The polymer is preferablynon-reactive with the HMG-CoA reductase inhibitor, i.e., no chemicalreaction occurs when the two are mixed. The polymer may be a polymerhaving no functional groups. Alternatively, the polymer may be onehaving functional groups, but none that are reactive with the HMG-CoAreductase inhibitor. The polymer may include a biodegradable polymer.For example, the polymer may include a polymer selected from the groupconsisting of polyhydroxy acids, polyanhydrides, polyphosphazenes,polyalkylene oxalates, biodegradable polyamides, polyorthoesters,polyphosphoesters, polyorthocarbonates, and blends or copolymersthereof. The polymer may also include a biostable polymer, alone or incombination with a biodegradable polymer. For example, the polymer mayinclude a polymer selected from the group consisting of polyurethanes,silicones, polyacrylates, polyesters, polyalkylene oxides, polyalcohols,polyolefins, polyvinyl chlorides, cellulose and its derivatives,fluorinated polymers, biostable polyamides, and blends or copolymersthereof.

At least certain embodiments of the invention provide a coated stentcomprising a stent having a coating composition that includes abiologically active component and a biodegradable, low-melting carriercomponent. Accordingly, in one embodiment, the invention provides astent having a coating composition comprising a biologically activecomponent and a biodegradable carrier having a melting point of about50° C. or less, more preferably about 45° C. or less. More particularly,the biodegradable carrier component has a melting point of from about10° C. to about 50° C., more preferably from about 35° C. to about 45°C. In other specific embodiments, the invention provides a coated stentcomprising a stent and a coating composition that includes a bioactivecomponent and a biodegradable liquid carrier component having aviscosity of from about 0.1 to about 15,000 centipoise, and morepreferably from about 0.1 to 5000 centipoise (cP). In yet anotherspecific embodiment, the invention includes a stent with a coatingcomposition that is in a solid state at room temperature (22° C.)outside a human body and that melts to form a liquid inside a humanbody.

In another embodiment, the coating composition comprises an effectiveamount of a non-polymeric carrier. In a particular embodiment, thenon-polymeric carrier comprises a fatty acid. The non-polymeric carriermay alternatively comprise a biocompatible oil, wax, or gel. In a yetfurther embodiment, the non-polymeric carrier may comprise a mixture ofone or more of a fatty acid, an oil, a wax, and/or a gel.

Coating compositions according to the present invention are preferablyhydrophobic. More preferably, the biodegradable carrier component of thecoating composition is hydrophobic. The carrier component is alsopreferably biocompatible. The biodegradable carrier may comprise apolymer. When the biodegradable carrier.

In another aspect, the invention can include a method of coating astent. In a specific embodiment, the method includes providing a coatingcomposition comprising a blend of a substantially unreacted HMG-CoAreductase inhibitor and a polymeric or nonpolymeric carrier, andapplying the coating composition to the stent. Providing the coatingcomposition may include mixing the HMG-CoA reductase inhibitor and anonpolymeric liquid carrier. In one embodiment, the nonpolymeric liquidcarrier comprises a C-6 to C-18 fatty acid. In another embodiment,providing the coating composition may include mixing the HMG-CoAreductase inhibitor and a polymeric liquid carrier. In a furtherembodiment, providing the coating composition may include mixing theHMG-CoA reductase inhibitor, a polymer, and a solvent under conditionssuch that the HMG-CoA reductase inhibitor does not chemically react withthe polymer, or does not react to any substantial extent. Providing thecoating composition may also include mixing the HMG-CoA reductaseinhibitor, a polymer, and a solvent at a temperature of from about 20°C. to about 30° C., preferably at about 25° C. The method of coating thecomposition may further comprise removing the solvent by, e.g., drying.In another embodiment, providing a coating composition may includeproviding a solid coating comprising an HMG-CoA reductase inhibitor anda polymer.

In another specific embodiment, the invention includes a method thatcomprises providing a coating composition that includes a biologicallyactive component and a biodegradable carrier component which has aviscosity of from about 0.1 to about 15,000 cP, and applying the coatingcomposition to the stent.

In another embodiment, a method of coating a stent may further compriseexpanding the stent to an expanded position before applying the coatingcomposition to the stent. The coating composition may be applied to thestent by any number of ways, e.g., by spraying the coating compositiononto the stent, by immersing the stent in the coating composition, or bypainting the stent with the coating composition. Other coating methods,such as electrodeposition can also be used. In one embodiment, excesscoating composition is allowed to drain from the stent. In anotherembodiment, the stent is dried after the coating composition is appliedto the stent to provide a solid coating composition. The coatingcomposition may be formed into a solid film that is then applied to thestent by wrapping the film around the stent. In preferred embodiments,the coating is applied with the bioactive component dissolved in thecarrier component. In alternative embodiments, the carrier component maybe applied to the stent and the bioactive component applied to thecarrier. In another alternative embodiment, the bioactive component maybe applied to the stent and the carrier component applied to thebioactive component.

In one or more specific embodiments, the invention can include atreatment method, comprising inserting a coated stent into a body lumenof a person, the coated stent comprising a stent and a coatingcomposition comprising a biodegradable carrier component and abiologically active component, the biodegradable carrier componenthaving a melting point of about 50° C. or less, more preferably 45° C.or less. In other specific embodiments, the coated stent provides astent and a coating composition comprising a biodegradable carriercomponent and a biologically active component, the carrier componenthaving a viscosity of from about 0.1 to about 15000 cP, or from about0.1 to about 5000 cP. In yet another specific embodiment, the coatedstent comprises a stent and a coating composition that comprises abiodegradable carrier component and a biologically active component, andthe coating composition (or at least the carrier component thereof) isin a solid state outside of a human body and a liquid inside of a humanbody.

In another aspect, the invention can include a treatment method,comprising attaching a stent to a catheter, spraying the catheter andthe stent with a coating composition comprising a biodegradable carriercomponent, and a biologically active component having a melting point ofabout 50° C. or less, and inserting the coated stent into a body lumenof a person.

In another aspect, the invention can include a coated stent, comprisinga stent and a coating composition comprising a biologically activecomponent and a biodegradable carrier component which may have a meltingpoint of about 50° C. or less, and a catheter which can be coupled tothe coated stent to form a treatment assembly.

In another aspect, the invention includes a method of treating anoccluded artery comprising providing a stent, providing a coatingcomposition comprising a nonpolymeric or polymeric carrier and a HMG-CoAreductase inhibitor in an amount effective to prevent or substantiallyreduce restenosis, applying the coating composition to the stent, anddeploying the stent in the occluded artery at the site of occlusion.Providing a coating composition may comprise dissolving or suspending anamount of the HMG-CoA reductase inhibitor effective to prevent orsubstantially reduce restenosis in a nonpolymeric carrier that is aliquid at room and/or body temperature. In another embodiment, providinga coating composition may comprise dissolving in a polymeric carrierthat is a liquid at room and/or body temperature an amount of theHMG-CoA reductase inhibitor effective to prevent or substantially reducerestenosis in an occluded vascular lumen. In alternative embodiments,the nonpolymeric or polymeric carrier may be a solid at room and bodytemperature. Where a polymeric carrier is provided, the HMG-CoAreductase inhibitor may be physically bound to the polymer, chemicallybound to the polymer, or both. The coating composition may be a solutionwhich includes the HMG-CoA reductase inhibitor, the polymer, and asolvent. The solvent may be removed by, e.g., drying the stent or othermethods known in the art to yield a stent having a solid polymericcarrier for the HMC-CoA reductase inhibitor. The coating composition mayinclude an amount of the HMG-CoA reductase inhibitor that istherapeutically effective for inhibiting regrowth of plaque orinhibiting restenosis. More particularly, the coating composition mayinclude from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,based on the total weight of the coating composition.

In another aspect, the invention can include a method of treatingrestenosis, comprising inserting a coated stent into a body lumen, thecoated stent comprising a stent and a coating composition comprising asubstantially unreacted HMG-CoA reductase inhibitor and a nonpolymericor polymeric carrier, which may be a liquid at room and bodytemperature, a solid at room and body temperature, or a solid at roomtemperature and a liquid at body temperature. In one embodiment, thecoated stent releases the HMG-CoA reductase inhibitor in an amountsufficient to inhibit or reduce the regrowth of plaque. In anotherembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount sufficient to inhibit or reduce restenosis.

In another aspect, the invention can include a method of localizeddelivery of an HMG-CoA reductase inhibitor, comprising inserting acoated stent into a body lumen, the coated stent comprising a stent anda coating composition comprising a substantially unreacted HMG-CoAreductase inhibitor and a polymeric or nonpolymeric carrier. In oneembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount effective to inhibit the regrowth of plaque. In anotherembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount effective to inhibit restenosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section of an artery experiencing restenosis in thepresence of an uncoated stent.

FIG. 2 is a cross-section of an artery containing a coated stent.

FIG. 3 is a stent of a type suitable for use in connection with thepresent invention.

FIG. 4 is a UV-VIS spectra of cerivastatin released from a stentcoating.

FIG. 5 is a release profile of cerivastatin released from a stentcoating of EVA film.

FIG. 6 is a release profile of cerivastatin released from a stentcoating of polycaprolactone film.

FIG. 7 is a release profile of cerivastatin released from a stent coatedwith silicone.

FIG. 8 is a release profile of cerivastatin released from a stent coatedwith liquid vitamin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

An exemplary artery 10 experiencing restenosis is shown in FIG. 1. Theendothelium 12 normally serves as a solid barrier between the layer ofsmooth muscle cells 14 and the arterial lumen 20. Small tears 16 in theendothelium 12 can expose smooth muscle cells 14, which can then migrateinto the arterial lumen 20 and hyperproliferate into a mass 18 which canpartially or completely occlude the lumen 20 even though an uncoatedstent 21 is placed, during a procedure such as angioplasty, in theartery 10 to keep the arterial lumen 20 open.

An artery 10 containing a coated stent 22 prepared according to anembodiment herein is shown in FIG. 2. The stent has a coating 24containing a carrier and a bioactive compound that inhibits restenosis.By using a stent having this coating 24, the tears 16 shown in FIG. 1 inthe endothelium 12 may be reduced or eliminated. Additionally, the mass18 created by a proliferation of smooth muscle cells 14, as shown inFIG. 1, is eliminated or substantially reduced.

FIG. 3 illustrates a stent 21 suitable for use in connection with thepresent invention. In one embodiment, the stent 21 comprises a hollowreticulated tube. The tubular body of stent 21 is defined by a number offilaments or struts 25 which surround open cells 26. The stent 21comprises an inner surface 27 facing the interior of the stent and anouter surface 28 facing the exterior. In a preferred embodiment, acoating (now shown) covers both the inner surface 27 and the outersurface 28. In alternative embodiments, the coating may cover only theinner surface, only the outer surface, or portions of one or both of theinner and outer surfaces. The coating may aggregate at the intersectionof filaments. In a preferred embodiment, the coated stent 22 (FIG. 2) ismade out of a metal or metal alloy, such as titanium, tantalum,stainless steel, or nitinol. In a preferred embodiment, the coating 24is made by mixing together an HMG-CoA reductase inhibitor, and a carrierin which both the HMG-CoA reductase inhibitor is soluble. In aparticularly preferred embodiment, the carrier is a liquid oil thatadheres to the inner and outer surfaces 27, 28 of the stent 22. In otherembodiments, the carrier comprises a polymer dissolved in a solvent,which is then removed, e.g., by drying, to yield a solid coatingcomposition comprising the polymer and the HMG-CoA reductase inhibitor.

At least certain embodiments of the invention include a coated stentcomprising a stent and a coating composition that includes abiologically active component and a biodegradable carrier componenthaving a melting point of about 50° C. or less. Preferably, thebiodegradable component has a melting point of from about 10° C. toabout 50° C., and most preferably, from about 35° C. to about 45° C. Inother specific embodiments, the invention provides a coated stentcomprising a stent and a coating composition comprising a bioactivecomponent and a liquid biodegradable carrier component that has aviscosity of from about 0.1 to about 15000 cP, and more preferably, fromabout 0.1 to about 5000 cP. In yet another specific embodiment, theinvention includes a stent with a coating composition that is in a solidstate at room temperature (22° C.) a human body and that melts to form aliquid inside a human body at body temperature (37° C.).

In a preferred embodiment, the coating 24 (FIG. 2) is made by mixingtogether a biologically active component (e.g., a restenosis-inhibitingagent) and a carrier in which the biologically active component issoluble. In a particularly preferred embodiment, the carrier is a liquidoil that adheres to the inner and outer surfaces 27, 28 of the stent 21(FIG. 3). In other embodiments, the carrier comprises a low-meltingpolymer dissolved in a solvent, which is then removed by, e.g., drying,to yield a solid coating composition comprising the polymer andbioactive component, which may comprise a restenosis inhibiting agentsuch as an HMG-CoA reductase inhibitor.

As discussed, the coated stent of this invention includes a stent and acoating composition. The coating composition is preferably a blend of abiologically active component, e.g., an HMG CoA reductase inhibitor anda liquid oil capable of adhering to the inner surface 27 and/or theouter surface 28 of the stent 22. In another embodiment, the coatingcomposition comprises a blend of HMG-CoA reductase inhibitor and apolymer. These two ingredients are preferably blended, e.g., mixedthoroughly but not chemically reacted to any substantial degree.Preferably the HMG-CoA reductase inhibitor is “substantially unreacted.”The term “substantially unreacted,” when referring to the HMG-CoAreductase inhibitor, means that the inhibitor does not chemically reactwith the oil, the polymer or any other component of the coating or thestent, to any degree that substantially reduces its biological activity,such as inhibiting restenosis by, e.g., inhibiting the proliferation ofsmooth muscle cells 14. Where the coating comprises a polymer, thereductase inhibitor is physically bound to the polymer and/or to thestent, but is not chemically bound to any significant degree. In apreferred embodiment, the carrier, whether liquid or solid, polymeric ornonpolymeric, is incapable of reacting chemically with the inhibitor,i.e., is totally non-reactive (inert) with respect to the inhibitor.

In another embodiment the coating composition described herein ispreferably a blend of a biologically active component and abiodegradable low-melting carrier component. The terms “biologicallyactive” and “bioactive” refer to a substance having an effect on aliving organism. See generally, Merriam Webster's Collegiate Dictionary(10^(th) ed., 2001). Preferably, the effect of a bioactive compound istherapeutic in nature. The term “biodegradable” as used herein refers toa substance that breaks down into non-toxic byproducts which areeliminated by the body. The term “low-melting” refers to a compositionhaving a melting point of 50° C. or less. Carrier compositions havingmelting points below 50° C. allow liquid-form delivery of a bioactivecomponent to a body lumen either with no heat at all (because thecomposition is a liquid at body temperature) or with relatively benignheating without denaturing or other harm to the patient. In anotherembodiment, the coating composition is a blend of a bioactive componentand a low-melting carrier comprising a biodegradable component, abiostable component, or both. In yet another embodiment, the coatingcomposition is a liquid carrier that is biodegradable or biostable.

An important aspect of the coating compositions of the present inventionis the melting point of the biodegradable component. Preferably, thebiodegradable component has a melting point of 50° C. or less, and morepreferably from about 35° C. to about 45° C. The term “melting point”refers generally to the temperature at which a pure substance's crystalsare in equilibrium with the liquid phase at atmospheric pressure. Seegenerally, Hawley's Condensed Chemical Dictionary (11^(th) Ed., 1987).Whenever melting points are discussed or referred to herein inquantitative terms, the melting point is measured according todifferential scanning calorimetry or other standard methods shown inanalytical or organic chemistry textbooks (see, e.g., AnalyticalChemistry Handbook, Section 15, J. A. Dean, McGraw-Hill, Inc., 1995).

Another important aspect of certain embodiments of the invention is thebiodegradable carrier component. In a preferred embodiment of thisinvention, the carrier component of the coating composition is orincludes one or more non-polymeric, biodegradable compounds ormaterials, which either contain no polymers at all or containessentially no polymers. For example, the carrier component shouldcontain less than 50% by weight polymer, preferably less than 25 wt %polymer, more preferably less than 10 wt %, and most preferably lessthan 1 wt % polymer material. The biodegradable carrier component ispreferably homogeneous (single phase) and may comprise a mixture ofcomponents that exist together as a solution, but which mayalternatively be a multiple phase blend. Examples of preferrednon-polymeric biodegradable carriers include liquid oleic acid, vitaminE, peanut oil, and cottonseed oil, which are liquids that are bothhydrophobic and biocompatible.

The biologically active component, e.g., an HMG-CoA reductase inhibitor,should remain active even after being coupled to the carrier to form thecoating composition and even after the coating composition is applied tothe stent and the device is sterilized. Preferably, the bioactivecomponent remains active when the coated stent is introduced into thebody of a patient, e.g., through a lumen, and is also still active whenit is released from the stent. An “effective amount” of the HMG-CoAreductase inhibitor means an amount that is sufficient, when deliveredto a localized area in the body lumen of a patient, to inhibit theproliferation of smooth muscle cells in a body lumen of a patient. An“effective amount” of the carrier means an amount of carrier sufficientto dissolve or suspend an effective amount of the bioactive component,and to provide an amount of the coating composition to substantiallycoat the portion of the stent that is desired to be coated, preferablythe entire stent. Preferably, the carrier has no functional groups thatreact with the bioactive component, e.g., an HMG-CoA reductaseinhibitor, under the conditions of forming the blend of the HMG-CoAreductase inhibitor and the carrier. The term “biodegradable” is appliedherein to any carrier, whether polymeric or nonpolymeric, and whetherliquid or solid, that breaks down in the body. The term “biostable” isapplied herein to any carrier, whether polymeric or nonpolymeric, andwhether liquid or solid, that does not break down in the body. The term“biocompatible” describes any material that is not harmful to and doesnot cause an immunological response in a body, e.g., a human being.

In accordance with methods and compositions described herein, restenosismay be prevented or lessened using localized delivery of HMG-CoAreductase inhibitors from a stent placed in a body lumen. Preferably,metal stents are coated with a biocompatible coating compositioncomprising a carrier containing an effective amount of an HMG-CoAreductase inhibitor. The coated stent can be deployed during anyconventional percutaneous transluminal angioplasty (PTA) procedure.Controlled delivery from a stent of the active HMG-CoA reductaseinhibitor, using a stent such as that described herein, in an effectiveamount, can inhibit the regrowth of plaque and prevent restenosis. Whilethe stents shown and described in the various embodiments are vascularstents, any type of stent suitable for deployment in a body lumen of apatient may be used with the coatings described herein.

An important aspect of this invention is the carrier used to form thecoating composition. The coating composition may comprise more than onecompound in a liquid carrier. The coating composition may alternativelycomprise more than one solid compound in a solid carrier. The coatingcomposition may further comprise both a liquid carrier and a solidcarrier. In a still further aspect, the coating composition may alsocomprise more than one type of nonpolymeric or polymeric compound in thecarrier, and may further comprise both a polymeric material and anonpolymeric material in a solid or liquid carrier. In a yet furtheraspect of the invention, the coating composition may comprise more thanone type of HMG-CoA reductase inhibitor. In coatings created by thismethod, the HMG-CoA reductase inhibitors are preferably physically boundto the carrier but not chemically bound thereto. Accordingly, thechemical or molecular structure of the HMG-CoA reductase inhibitor ispreferably unchanged when they are mixed with the polymers to form thecoating. Therefore, when the HMG-CoA reductase inhibitor is releasedfrom the coating, it remains in the desired active form.

As used herein, the terms “liquid” and “solid” are defined according totheir broadest recognized definitions. Unless stated otherwise, amaterial is determined to be a “liquid” or “solid” at room temperature,i.e., 22° C. The term “liquid,” when referring to carriers and coatingcompositions according to the present invention, includes a fluid (aswater) that has no independent shape but has a definite volume, does notexpand indefinitely and is only slightly compressible. The term “liquid”also includes any amorphous (e.g., noncrystalline) form of matterintermediate between gases and solids in which the molecules are muchmore highly concentrated than in gases but much less concentrated thanin solids. See, generally, Hawley's Condensed Chemical Dictionary,(11^(th) Ed., 1987). As discussed in further detail below, an amorphousliquid having a high viscosity can be used to advantage in compositionsaccording to the present invention. The term “solid,” when referring tocarriers and coating compositions, includes a substance that does notflow perceptibly under moderate stress, has a definite capacity forresisting forces (e.g., compression or tension) which tend to deform it,and, under ordinary conditions, retains a definite size and shape. Seegenerally, Merriam Webster's Collegiate Dictionary (10^(th) ed., 2001).

The coating composition, including the bioactive component and thecarrier, should be non-fragmentary. That is, the coating compositionpreferably does not break down into solid, potentially harmful fragmentswhen the coated stent is in the body. In certain embodiments, thebiodegradable carrier is a liquid when it is part of the coatingcomposition residing on the stent outside the body. This liquid isincapable of breaking down into solid, potentially harmful fragments. Inother embodiments, the biodegradable carrier is a solid that preferablybecomes a liquid when introduced to the body (or shortly thereafter).For example, the carrier can be a solid at typical ambient temperatures(i.e., from 20° C. to 30° C.), and is preferably a solid at about 22°C., i.e., room temperature. It should, however, become a liquid at thetemperature of a human body, which is approximately 37° C. In otherwords, the biodegradable component may be a solid outside a human bodyand a liquid inside a human body, so that it melts to form a liquid wheninside the body. It is also contemplated that one skilled in the art mayblend a biodegradable compound which is solid at typical ambienttemperatures (or room temperature) with other components to form acarrier which can be either a liquid at ambient temperatures (or roomtemperature) or a liquid at the temperature of a human body.

In yet a further embodiment of the present invention the coatingcomposition comprises a nonpolymeric compound that is a solid at roomtemperature but becomes a liquid at or near body temperature. Inparticular, the coating composition comprises low molecular weight waxesand derivatives having a melting point at between about 30° C. and 40°C., more particularly from about 35° C. to 40° C. and more particularlyabout 36° C. to about 38° C. In preferred embodiments, the low meltingsolid is applied to the stent by heating the solid to above its meltingpoint, then sprayed, painted, dipped, molded, or otherwise applied tothe stent as a liquid and allowing the liquid to resolidify upon coolingat ambient temperatures.

In another embodiment, two or more types of biodegradable compounds(polymers or non-polymers) may be blended together to obtain a liquidcarrier for use in the coating composition. The biodegradable compoundscan be liquids before they are mixed together, e.g., forming ahomogeneous solution, mixture, or suspension. Alternatively, some of thebiodegradable compounds may be solids before they are mixed with otherliquid biodegradable compounds. The solid biodegradable compoundspreferably dissolve when they are mixed with the liquid biodegradablecompounds, resulting in a liquid carrier composition containing thedifferent biodegradable compounds. In another embodiment, thebiodegradable carrier component of the coating composition is a solid,which dissolves when mixed with the biologically active component andany other components included in the coating composition.

In certain specific embodiments, an important aspect of thebiodegradable carrier component is its viscosity. Generally, viscosityis a term that refers to thickness or resistance to flow. Inquantitative terms, the biodegradable component should have a viscosityof from about 0.1 to about 15000 cP. A person skilled in the polymerchemistry art can use Brookfield viscometer to measure viscosity ofvariety of fluids. Whenever viscosity is discussed herein inquantitative terms, the term “viscosity” is defined according to an ASTMmethod describing viscosity measurement can be found in Test MethodD2983-87 entitled “Standard Test Method for Low-Temperature Viscosity ofAutomotive Fluid Lubricants Measured by Brookfield Viscometer.”

Preferably, liquid stent coatings, such as those made from the materialsdescribed herein, have sufficient viscosity to withstand blood and otherbody fluids flowing against them without being washed off a stent, bothduring the insertion of the stent into the body and after theimplantation of the stent at the desired site. Accordingly, in apreferred embodiment, the biodegradable carrier is a highly viscousliquid, e.g., an amorphous or even a “slimy” material that forms aliquid coating on the stent. A viscosity of from about 0.2 to about 200cP is preferred. Preferably, the viscosity of the biodegradable carrierresults in a coating that is less likely to be removed from the stent bythe shear forces created by blood flow past the stent than a coatingincluding a biodegradable carrier having a lower viscosity. The variousviscosities discussed herein are measured at 20° C.

In order to create coatings in which HMG-CoA reductase inhibitors arephysically rather than chemically bound to the polymers in the coatings,HMG-CoA reductase inhibitors and carriers are chosen such that they willnot have functional groups that will react with each other under thecompounding conditions of to form the coating solution.

The carriers in the coating composition may be either biodegradable orbiostable. Biodegradable polymers are often used in syntheticbiodegradable sutures. These polymers include polyhydroxy acids.Polyhydroxy acids suitable for use in the present invention includepoly-L-lactic acids, poly-DL-lactic acids, polyglycolic acids,polylactides including homopolymers and copolymers of lactide (includinglactides made from all stereo isomers of lactic acids, such as D-,L-lactic acid and meso lactic acid), polylactones, polycaprolactones,polyglycolides, polyparadioxanone, poly 1,4-dioxepan-2-one, poly1,5-dioxepan-2-one, poly 6,6-dimethyl-1,4-dioxan-2-one,polyhydroxyvalerate, polyhydroxybuterate, polytrimethylene carbonatepolymers, and blends of the foregoing. Polylactones suitable for use inthe present invention include polycaprolactones such aspoly(e-caprolactone), polyvalerolactones such as poly(d-valerolactone),and polybutyrolactones such as poly(?-butyrolactone). Otherbiodegradable polymers that can be used are polyanhydrides,polyphosphazenes, biodegradable polyamides such as syntheticpolypeptides such as polylysine and polyaspartic acid, polyalkyleneoxalates, polyorthoesters, polyphosphoesters, and polyorthocarbonates.Copolymers and blends of any of the listed polymers may be used. Polymernames that are identical except for the presence or absence of bracketsrepresent the same polymers.

Biostable polymers that are preferred are biocompatible. Biostablepolymers suitable for use in the present invention include, but are notlimited to polyurethanes, silicones such as polyalkyl siloxanes such aspolydimethyl siloxane and copolymers, acrylates such as polymethylmethacrylate and polybutyl methacrylate, polyesters such aspoly(ethylene terephthalate), polyalkylene oxides such as polyethyleneoxide or polyethylene glycol, polyalcohols such as polyvinyl alcoholsand polyethylene glycols, polyolefins such as polyethylene,polypropylene, poly(ethylene-propylene) rubber and natural rubber,polyvinyl chloride, cellulose and modified cellulose derivatives such asrayon, rayon-triacetate, cellulose acetate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose etherssuch as carboxymethyl cellulose and hydroxyalkyl celluloses, fluorinatedpolymers such as polytetrafluoroethylene (Teflon), and biostablepolyamides such as Nylon 66 and polycaprolactam. Fixed animal tissuessuch as glutaraldehyde fixed bovine pericardium can also be used.Polyesters and polyamides can be either biodegradable or biostable.Ester and amide bonds are susceptible to hydrolysis, which cancontribute to biodegradation. However, access to water, and thus,hydrolysis, can be prevented by choosing certain neighboring chemicalstructures.

In a preferred embodiment, the polymer used to form the coatingcomposition is polycaprolactone. Polycaprolactone is biocompatible, andit has a low glass transition temperature, which gives it flexibly andallows it to withstand the temperature changes stents often experienceduring their formation and use. For example, nitinol stents arepreferably cooled to a temperature of about −50° C. so that they becomeflexible and can be compressed and fitted onto a catheter. A sheathplaced over the stent (or another restraint such as a wire binding theends of the stent), prevents the stent from expanding as it isintroduced into a patient's body at a higher temperature. The sheath orother restraint is removed at the site of the stent's use, and the stentre-expands to the size at which it is coated with a composition thatincludes polycaprolactone. Polycaprolactone, unlike some other stentcoating materials, does not become brittle and crack throughout thesefluctuations in stent temperature and size. Preferably, thepolycaprolactone has a molecular weight between about 20,000 and2,000,000, and provides a stronger and more uniform coating than lowermolecular weight polymers.

Generally, the bioactive component, e.g., an HMG-CoA reductase inhibitoris released from the stent by diffusion of the HMG-CoA reductaseinhibitor out of the carrier. If the carrier comprises a biodegradablepolymer, the bioactive component is preferably released from the stentby the degradation of the polymer. A controlled release of the bioactivecomponent from the coating can be achieved with a carrier comprisingboth a liquid and a solid through the relatively rapid release of thediffusion of the bioactive component from the liquid and a slowerrelease from the solid. In a still further embodiment, a highlycontrolled delivery of the bioactive component can be achieved by acarrier comprising a liquid, a biodegradable (preferably solid) polymer,and a biostable (preferably solid) polymer. An initial release of thebioactive component from the liquid may be followed by a slower releasefrom the biodegradable solid, and a still slower release from thebiostable solid.

The diffusion rate of the bioactive component, e.g. an HMG-CoA reductaseinhibitor, from the carrier can be determined by release studies and thedose can be adjusted to deliver the drug at a desired rate. In oneembodiment, a higher dose of the bioactive component can be deliveredover a short period of time by using a liquid that releases a knownamount of the inhibitor within one to three days. In another embodiment,a higher dose of bioactive component can be delivered over a shortperiod of time by using a nonpolymeric liquid carrier such as vitamin E.In another embodiment, the bioactive component can be delivered via abiodegradable polymer that degrades within a few days, e.g., lowmolecular weight polyglycolic acid, releasing the bioactive component byboth diffusion and/or coating degradation. In another embodiment, abiodegradable polymer which delivers an HMG CoA reductase inhibitorprimarily through diffusion is used. An example of such a polymer ispolycaprolactone, which degrades after several years in the body. Inanother embodiment, the carrier may comprise a nonpolymeric liquid and abiodegradable polymer that is a solid at room temperature ad a liquid atbody temperature.

Advantageously, the rate of release of a bioactive component from aliquid coating can be more easily predicted and is more consistent thanthe rate of release of a drug from other coatings in which the drug ischemically bound to the coating. With the coatings described herein, thebioactive component(s) are preferably physically released from thecoatings, and thus, not dependent on a chemical step, such ashydrolysis, whose rate could vary in different patients as well aswithin the same patient.

In at least certain embodiments the coating compositions of the presentinvention release their biologically active components in the body bothby diffusion of the bioactive compounds from the coatings and bydegradation of the coatings. For coating compositions that degradewithin a few days or weeks in the body, much of the release of thebiologically active components occurs in this time frame. Thistime-release feature is advantageous because it is believed that a highdose of a biologically active component, such as an anti-restenosiscompound or an antibiotic, delivered quickly can often be more effectivethan a lower dose delivered over a longer period of time. For example,bacterial infections are often treated with high doses of antibiotics assoon as the infection is detected. A high initial dose of antibioticsmay kill all of the bacteria, whereas a lower dose of antibioticsadministered over a longer period of time often results in the selectionfor, and survival of, bacteria that can survive in the presence of a lowdose of the drug. Similarly, it is contemplated that if a lowconcentration of a biologically active component, such as a restenosisinhibitor which inhibits smooth muscle cell proliferation, is releasedslowly from a stent, some smooth muscle cells will still be able toproliferate and partially occlude the artery. Then, when the supply ofthe biologically active component is exhausted, this small group ofsmooth muscle cells will continue to proliferate and block a largerpercentage of the arterial lumen. It is contemplated that this situationcan be avoided or minimized using coating compositions described herein,because it is believed that the liquid coatings will be removed from thestent and degraded within a few days or weeks, and thus deliver alocalized, high dose of a biologically active component in a shortperiod of time.

The liquid coating compositions described herein which are made frombiodegradable materials will degrade in the body and be removed from theangioplasty balloon or stent. When these coating compositions degrade,they typically degrade into their molecular subunits without creatingfragments that may irritate or damage the endothelium and lead torestenosis, possibly in areas remote from the site of stent deployment.Thus, these coating compositions provide safe, temporary coatings forstents. Also, the coatings typically provide a smooth surface forstents, which minimizes abrasion or tearing damage to the endothelium bystents during and after their implantation in the body. It iscontemplated that minimizing damage to the endothelium minimizes thelikelihood of the development of restenosis. The coating compositionsmay also protect the stent itself from chemical or physical damage inthe body.

The coating composition comprising the carrier and the HMG-CoA reductaseinhibitor can be applied to a stent in a number of different ways.Preferably, a stent is coated in its expanded form so that a sufficientamount of coating will be applied to coat the expanded stent. In apreferred embodiment, the coating composition is at least initiallyapplied to the stent as a liquid. Spraying the stent with the liquidcarrier results in a coating of uniform thickness on the struts of thestent. Where the coating composition comprises a solid polymer, thepolymer is preferably dissolved in a suitable solvent to form a polymersolution and the stent is sprayed with the solution in order to coat thestent struts. Alternatively, the polymer solution may be painted on thestent or applied by other means known in the art, such aselectrodeposition, dipping, casting or molding. The solvent may then bedried to yield a solid coating composition comprising the polymer. Inone embodiment, the stent may be dip coated or immersed in the solution,such that the solution completely coats the struts of the stent. In eachof these coating applications, the entirety of both the outer and innersurfaces of the stent are preferably coated, although only portions ofeither or both surfaces may be coated in alternative embodiments. In oneembodiment, excess coating composition is allowed to drain from thestent. In another embodiment, the solvent may then be dried to yield asolid coating composition having a melting point of 50° C. or less,preferably at body temperature or less. In a preferred embodiment, thestent is dried at from 20° C. to 30° C. or ambient temperature for aperiod of time sufficient to remove the solvent. The drying temperatureshould not be high as to cause the polymer to react chemically with theHMG-CoA reductase inhibitor.

Multiple layers of the polymer solution may be applied to the stent.Preferably, each layer is allowed to dry before the next coating isapplied. While an HMG-CoA reductase inhibitor is included in at leastone layer of the coating, the coating solution in the other layers mayoptionally also contain the same or a different HMG-CoA reductaseinhibitor. The polymer solution for each layer may contain the same ordifferent polymers. The number of layers and the polymers in the layerscan be chosen to deliver an HMG-CoA reductase inhibitor in a controlledmanner because the rate of diffusion of the HMG-CoA reductase inhibitorthrough a known thickness of polymers can be estimated or measureddirectly.

In one embodiment, a first layer of the polymer solution, e.g., a primerlayer, may be applied to improve the adhesion of the coating compositionto the stent surface. Generally, coating a stent by completelyencapsulating the struts of the stent is preferred. Completeencapsulation typically provides uniform distribution of a drug alongthe surfaces of the stent. A completely encapsulated coated stent isalso more resistant than a partially coated stent to peeling and othermechanical stresses encountered during stent deployment. In certainspecific embodiments, a top layer of the polymer solution without a drugmay be applied on the coating. The top coating may be used to controlthe diffusion of the drug from the stent. The thickness of the coatingis preferably 0.1 microns to 2 mm, more preferably from 1 to 100microns, even more preferably from 1 to 25 microns. More preferably, thethickness of the coating is from 1 to 50 microns. Most preferably, thethickness of the coating is from 10 to 30 microns. However, to provideadditional coating to effect release of higher doses of the bioactivecomponent, grooves, capillaries, channels or other depressions in thesurface of the stent or struts may be provided to increase the surfacearea and thereby provide sites of enhanced adhesion of the coating.

Specific embodiments of the invention include a stent with multiplecoatings or layers, e.g., films. For example, a stent with three or morecoatings or layers can be provided, where the first layer (contactingthe stent) comprises a first carrier material having substantially noHMG-CoA reductase inhibitor, the second layer (applied to the outersurface of the first layer) includes the HMG-CoA reductase inhibitor ina second carrier material, and the third layer (applied to the secondlayer) comprises a third carrier material having substantially noHMG-CoA reductase inhibitor.

In another embodiment, the polymer solution can be formed into a filmand the film then applied to the stent. Any of a variety of conventionalmethods of forming films can be used. For example, the polymer, HMG-CoAreductase inhibitor and solvent are preferably mixed into solution andthen poured onto a smooth, flat surface such that a coating film isformed after the solution is dried to remove the solvent. The film canthen be cut to fit the stent on which it is to be used. The film maythen be mounted, such as by wrapping, on the outer surface of a stent.

As used herein, the term “solvent” is defined according to its broadestrecognized definition and includes any material into which the carrierand/or the bioactive agent, e.g. the polymer and the HMG-CoA reductaseinhibitor can dissolve, fully or partially, at room temperature or from20° C. to 50° C. or from 20° C. to 40° C. Methylene chloride is apreferred solvent. Methylene chloride's low boiling point facilitatesremoval from the polymer and the HMG-CoA reductase inhibitor at ambienttemperatures by evaporation. However, it is contemplated that virtuallyany organic solvent that dissolves the polymer can be used. Solventsthat can cause corrosion, such as highly acidic or basic aqueoussolutions, are not preferred. Organic solvents that are biocompatible,have low boiling points and high flash points, are preferred. Othersolvents that may be used include chloroform, toluene, cyclohexane,acetone, methylethyl ketone, ethyl formate, ethyl acetate, acetonitrile,n-methylpyrrolidinone, dimethyl sulfoxide, n,n-dimethylacetamide,n,n-dimethyl formamide, ethanol, methanol, acetic acid, andsupercritical carbon dioxide.

In a particularly preferred embodiment, the coating compositioncomprises a nonpolymeric liquid that remains a liquid after it isapplied to the stent and the stent is deployed within the body of apatient, i.e., the coating liquid has a melting point below bodytemperature (37° C.), preferably below 30° C., more preferably belowroom temperature (22° C.), more preferably below 20° C., still morepreferably below 10° C. The liquid is preferably a viscous liquid thatadheres to at least a portion of the external surface 28 of the stent 22in sufficient quantity to deliver a therapeutically effective amount ofthe HMG-CoA reductase inhibitor upon expansion in the body of thepatient. Although the viscous liquid may be hydrophilic, in a preferredembodiment the viscous liquid is hydrophobic. Specifically, the carriermay comprise liquid Vitamin E and derivatives thereof, such as vitamin Eacetate and vitamin E succinate.

Biodegradable carriers and coating compositions according to the presentinvention are preferably hydrophobic so that the coating composition isnot immediately dissolved and washed off the stent in the aqueousenvironment of the body. Hydrophilic and water-soluble biodegradablecarriers and coating compositions may in some cases be used, but theyare less preferred because of their tendency to be dissolved and washedoff the stent more quickly than hydrophobic and water-insolublebiodegradable carriers and coating compositions. The term “hydrophobic”is defined according to its broadest recognized definition, and includesbeing antagonistic to water, and incapable of dissolving, or havinglimited solubility, in water. See generally, Hawley's Condensed ChemicalDictionary (11^(th) n Ed., 1987).

In another preferred embodiment, the viscous, hydrophobic liquidcomprises a C4-C36 fatty acid or mixtures of such fatty acids, such asoleic acid or stearic acid, by way of nonlimiting example. In yetanother preferred embodiment, the viscous, hydrophobic liquid comprisesan oil. Exemplary oils suitable for use in the present invention includepeanut oil, cottonseed oil, mineral oil, low molecular weight (C4-C36),and other viscous organic compounds that behave as oils such as, by wayof nonlimiting example, 1,2 octanediol and other low molecular weightalcohols and polyols. Olive oil has a viscosity of 84 cP at 20° C. Theviscosity of other materials is shown in Table 2 for reference purposes.

TABLE 2 Viscosity of various materials at 20° C. Viscosity SubstanceName (Centipoise) Water 1 Castor oil 986 Nylon resin melt 100000 Diethylether 0.23 Olive oil 84 Benzene 0.65

Spraying the stent with the liquid carrier results in a coating ofuniform thickness on the struts of the stent. In another embodiment, thestent may be dip coated or immersed in the solution, such that thesolution completely coats the struts of the stent. Alternatively, thestent may be painted with the solution, such as with a paint brush. Ineach of these coating applications, the entirety of both the outer andinner surfaces of the stent are preferably coated, although onlyportions of either or both surfaces may be coated in some embodiments.

In yet a further embodiment of the present invention the coatingcomposition comprises a nonpolymeric compound that is a solid at roomtemperature but becomes a liquid at or near body temperature. Inparticular, the coating composition comprises low molecular weight waxesand derivatives having a melting point at between about 30° C. and 40°C., more particularly from about 35° C. to 40° C. and more particularlyabout 36° C. to about 38° C. In preferred embodiments, the low meltingsolid is applied to the stent by heating the solid to above its meltingpoint, then sprayed, painted, dipped, molded, or otherwise applied tothe stent as a liquid and allowing the liquid to resolidify uponcooling. The stent may then be deployed in the body lumen, whereupon thecoating composition re-liquifies.

An important aspect of certain embodiments of the invention is thebiologically active component. One or more biologically activecomponents are included in the coating composition; preferably beforethe coating composition is applied to a stent. It is, however,contemplated that the biologically active component may in certain casesbe combined with the carrier to form the coating composition after thebiodegradable component is applied to the stent. As discussed above, thecoated stent may be used to deliver a bioactive material to a localizedarea in a body. Preferably, the biologically active component is onethat inhibits restenosis and/or prevents smooth muscle cellproliferation. Preferred examples of biologically active components arecomponents that inhibit cell growth by affecting one of the stepsinvolved in the cell cycle. Preferred components that affect the cellcycle are anticancer agents such as paclitaxel, immunosuppressantcompounds such as rapamycin, antibiotics such as actinomycin D, andHMG-CoA reductase inhibitors such as cerivastatin. Other bioactivecomponents forming part of the coating composition can include compoundssuch as antithrombin agents such as heparin and hirudin, calcium channelblockers such as colchicine, and compounds that promoteendothelialization such as nitric oxide or nicotine. In a preferredembodiment, the biologically active component is hydrophobic and iseasily dissolved in the biodegradable carrier to form a hydrophobicliquid coating composition. It is particularly preferred that thehydrophobic biologically active component(s) have a low molecularweight, i.e., a molecular weight below 2000, and more preferably below1000, which can be used to administer a localized treatment in the areaof stent deployment. The treatment may be for a condition such asrestenosis.

In embodiments in which a biologically active component is included inthe coating composition, the biologically active component itself may bea liquid. For example, vitamin E and nicotine (free base) are liquid atambient temperatures (see Table 1) and may potentially have ananti-restenosis therapeutic effect. Preferably, the liquid biologicallyactive component is biodegradable. In certain embodiments, the coatingcomposition may consist essentially of the biologically activecomponent, without a separate carrier component. In certain embodiments,the coating composition may consist of the biologically activecomponent.

TABLE 1 Bioactive compounds that are liquid or low melting solids(Sigma-Aldrich 2000 catalog) Physical Molecular appearance at weightambient Substance Name (Dalton) Molecular formula temperature Vitamin E431 C₂₉H₅₀O₂ Liquid Vitamin E acetate 473 C₃₁H₅₂O₃ Liquid Nicotine 162C₁₀H₁₄N₂ Liquid Nicotine 212 C₁₀H₁₄N₂•½H₂SO₄ Liquid Hemisulfate Salt

As discussed above, the coating composition comprises a bioactivecomponent and a biodegradable carrier component. Preferably, the coatingcomposition comprises from 0.1% to 100% by weight of a biologicallyactive component and from 1% to 99% by weight of a biodegradable carriercomponent. More preferably, the coating composition comprises from 0.1%to 50% by weight of a biologically active component and from 50% to99.9% by weight of a biodegradable carrier component. The coatingcomposition can be prepared in a number of ways including by simplymixing the bioactive component and the carrier component together toform a mixture, e.g., a solution or suspension. Alternatively, thebioactive component and the carrier component together are mixed in asuitable solvent, the coating is applied to the stent, and the solventis removed. Preferably the coating composition is applied to the stentin its expanded state.

Where a biologically active component is included in or on the coatingcomposition, the biologically active component may compromise an HMG-CoAreductase inhibitor. In certain specific embodiments, a coated stent cancomprise a stent and a coating composition comprising a substantiallyunreacted HMG-CoA reductase inhibitor and a carrier. The carrier in thecoating composition may be either biodegradable or biostable.

In one embodiment, the coating composition comprises a blend of anHMG-CoA reductase inhibitor and a liquid oil, which may be nonpolymericor polymeric, capable of adhering to the inner surface 27 and/or theouter surface 28 of a stent 21 as shown in FIG. 3. In anotherembodiment, the coating composition comprises a blend of an HMG-CoAreductase inhibitor and a polymer. These two ingredients are preferablyblended, e.g., mixed thoroughly but not chemically reacted to anysubstantial degree. Preferably the HMG-CoA reductase inhibitor issubstantially unreacted. The term “substantially unreacted,” whenreferring to the HMG-CoA reductase inhibitor, means that the inhibitordoes not chemically react with the oil, the polymer or any othercomponent of the coating or the stent, to any degree that substantiallyreduces its biological activity, such as inhibiting restenosis, e.g., byinhibiting the proliferation of smooth muscle cells 14. Where thecoating comprises a polymer, the reductase inhibitor is preferablyphysically bound to the polymer and/or to the stent, but not chemicallybound to any significant degree. In a preferred embodiment, the carrier,whether liquid or solid, polymeric or nonpolymeric, is incapable ofreacting chemically with the inhibitor, i.e., is totally non-reactive(inert) with respect to the inhibitor.

In a preferred embodiment, the HMG-CoA reductase inhibitor used in thecoating composition is cerivastatin. Cerivastatin is a very potentHMG-CoA reductase inhibitor. For example, when it is administeredsystemically, a therapeutic dose of cerivastatin is less than 1 mg perday, while other HMG-CoA reductase inhibitors must be administered in 50mg doses. A thinner stent coating can be used if cerivastatin is thechosen HMG-CoA reductase inhibitor instead of other HMG-CoA reductaseinhibitors because less coating is needed. For example, a stent coatingpreferably has a thickness of about 10-100 μm. If less drug and lesscoating to carry the drug are required, a stent coating having apreferable thickness of 10-25 μm can be used. A thinner stent coatingmay be preferred because it leaves more of the arterial lumen open forblood flow. Thinner coatings are also useful in preserving sidebranchaccess. Sidebranches are small blood vessels that branch out from thecoronary artery and provide blood to some part of the heart.

Cerivastatin has other properties, in addition to its ability to inhibitthe proliferation of smooth muscle cells that can contribute torestenosis, making it a desirable component of stent coatings. Forexample, cerivastatin has anti-thrombotic activity. Stents can often besites of thrombus formation in the body because of theimmunologically-triggered aggregation of different cell types and bloodcomponents at the site of a foreign object in the body. Thus, includingcerivastatin in a stent coating may help prevent thrombus formation atthe site of the stent. Cerivastatin also promotes endothelialization, orthe repair of the endothelium 12 after it is damaged, such as by thedelivery and expansion of the stent in an artery or other body lumen. Itis contemplated that the endothelialization triggered by cerivastatincan help repair the endothelium, and thus reduce tears in theendothelium through which smooth muscle cells and other cell types canmigrate into the arterial lumen and proliferate, leading to restenosis.

Other HMG-CoA reductase inhibitors may be used in these stent coatings.For example, atorvastatin, simvastatin, fluvastatin, lovastatin, andpravastatin may be used. While these compounds are known for theirantihypercholesterolemic properties, it is believed that they may haveother beneficial activities, such as restenosis inhibition or inhibitionof cell proliferation, when they are delivered in a localized manner,such as from a stent coating.

In one embodiment, the coating compositions described herein may includemore than one bioactive component, preferably more than one type ofHMG-CoA reductase inhibitor. For example, a coating composition mayinclude cerivastatin and lovastatin. In other specific embodiments, thestent coatings described herein may include one or more drugs orbioactive compounds that inhibit restenosis and are not HMG-CoAreductase inhibitors. These drugs include, but are not limited to,rapamycin, paclitaxel, actinomycin D, nicotine, and bioactivederivatives, analogues, and truncates of the foregoing. It iscontemplated that combining these drugs with an HMG-CoA reductaseinhibitor will provide a more effective coating composition forinhibiting restenosis than a coating composition containing only onerestenosis inhibiting agent. However, the foregoing may also be usedwithout an HMG-CoA reductase inhibitor.

In addition to stents, examples of other medical devices that can becoated in accordance with aspects of the inventions disclosed hereininclude catheters, heart valves, pacemaker leads, annuloplasty rings andother medical implants. In other specific embodiments, coatedangioplasty balloons and other coated medical devices can also compriseone of the coating compositions disclosed herein. However, stents arepreferred. The coating composition may be applied to the stent (or othermedical device) by any number of ways, e.g, by spraying the coatingcomposition onto the stent, by immersing the stent in the coatingcomposition, or by painting the stent with the coating composition.Preferably, a stent is coated in its expanded (i.e., enlarged diameter)form so that a sufficient amount of the coating composition will beapplied to coat the entire surface of the expanded stent. When the stentis immersed in the coating composition, the excess coating compositionon the surface of the stent may be removed, such as by brushing off theexcess coating composition with a paint brush. In each of these coatingapplications, preferably both the outer and inner surfaces of the stentare coated.

The coatings of the present invention are suitable for use on any knowncardiovascular stent such as, e.g., the Palmaz stent disclosed in U.S.Pat. Nos. 4,733,665 and 4,739,762. Other stents may also be used.Notwithstanding the foregoing, in a preferred embodiment, the coatingcompositions described herein are used on stents having struts, andfurther including a surface enhancing feature such as capillaries,grooves or channels in the struts, in which the coating composition cancollect and be retained by surface tension.

The coating compositions described herein preferably remain on a stent,partially or in substantial part, after the stent has been introduced tothe body, for at least several days and more preferably for severalweeks. In one or more specific embodiments, the coating composition is asolid until it is placed in the body together with the stent, at whichtime it begins to melt to form a liquid, e.g., at 37° C. Morepreferably, the coating composition does not melt immediately uponinsertion into the body, but melts upon reaching the site of its use.

As discussed above, one type of medical device suitable for use inconnection with coatings of the present invention is an angioplastyballoon. The liquid coating compositions described herein preferablyremain substantially intact on an angioplasty balloon during theinsertion of the balloon through the body to the site of its use. Someof the coating composition will be transferred from the balloon to thehydrophobic plaque at the occluded site in the artery when the balloonis inflated at the site of an artery blockage. This is advantageousbecause the biologically active component in the coating compositionwill be directly transferred with the carrier onto the plaque. In thismanner, the biologically active component can be delivered directly toits desired site of use. In a preferred embodiment, the coatingcompositions are hydrophobic. When hydrophobic coating compositions areused, they tend to dissolve faster than non-hydrophobic coatingcompositions after contacting the hydrophobic plaque and, thus, morereadily release the biologically active component.

In another aspect, the invention can include a method of coating astent. A specific embodiment of the method includes providing a stent,providing a coating composition comprising a biologically activecomponent and a carrier component that has a melting point of about 50°C. or less, more preferably about 40° C. or less, most preferably bodytemperature (37° C.) or less, and applying the coating composition tothe stent. In another embodiment, the invention includes a method thatcomprises providing a coating composition that includes a biologicallyactive component and a liquid carrier component which has a viscosity offrom about 0.1 to about 15000 cP, and applying the coating compositionto the stent.

In a specific embodiment, the method of coating a stent comprisesproviding a 36) stent, providing a coating composition comprising ablend of a substantially unreacted bioactive component and a polymericor nonpolymeric carrier having a melting point of about 50° C. or less,and applying the coating composition to the stent. Providing to thecoating composition may comprise mixing the bioactive component and anonpolymeric liquid carrier. In one embodiment, the nonpolymeric liquidcarrier comprises a C-6 to C-18 fatty acid, such as oleic acid orstearic acid. In another embodiment, the liquid carrier comprises aliquid selected from the group consisting of vitamin E, peanut oil,cottonseed oil, and mineral oil. In another embodiment, providing thecoating composition may comprise mixing the bioactive component and apolymeric liquid carrier. In a further embodiment, providing the coatingcomposition may include mixing an HMG-CoA reductase inhibitor, alow-melting polymer, and a solvent under conditions such that theHMG-CoA reductase inhibitor does not chemically react with the polymer,or does not react to any substantial extent, applying the mixture to thestent, and removing the solvent. Providing the coating composition mayalso include mixing the HMG-CoA reductase inhibitor, a polymer, and asolvent at a temperature of from about 20° C. to about 30° C.,preferably at about 22° C. In another embodiment, providing a coatingcomposition may include providing a solid coating comprising an HMG-CoAreductase inhibitor and a polymer.

In one or more specific embodiments, the invention can include atreatment method, comprising deploying a coated stent into a body lumenof a patient, the coated stent comprising a stent and a coatingcomposition that comprises a carrier component and a bioactivecomponent, the biodegradable component having a melting point of about50° C. or less. In a preferred embodiment, the carrier is biodegradable,although biostable carriers may also be used. In other specificembodiments, the coated stent comprises a stent and a coatingcomposition that includes a carrier component and a bioactive component,the carrier having a viscosity of from about 0.1 to about 15000. In yetanother specific embodiment, the coated stent comprises a stent and acoating composition that includes a biodegradable carrier component anda bioactive component, and the carrier is in a solid state outside of ahuman body and a liquid inside of a human body.

In another aspect, the invention can include a treatment methodcomprising attaching a stent to a catheter, applying to the catheter andthe stent a coating composition comprising a biodegradable carriercomponent having a melting point of about 50° C. or less and a bioactive component, and deploying the coated stent into a body lumen of apatient.

In another aspect, the invention includes a method of treating anoccluded artery comprising providing a stent, providing a coatingcomposition comprising a low-melting nonpolymeric or polymeric carrierand a bioactive component in an amount effective to prevent orsubstantially reduce restenosis, applying the coating composition to thestent, and deploying the stent in the occluded artery at the site ofocclusion. Providing a coating composition may comprise dissolving orsuspending in a nonpolymeric liquid or low-melting carrier an amount ofan HMG-CoA reductase inhibitor effective to prevent or substantiallyreduce restenosis. In another embodiment, providing a coatingcomposition may comprise dissolving in a polymeric liquid or low-meltingcarrier an amount of an HMG-CoA reductase inhibitor effective to preventor substantially reduce restenosis in an occluded vascular lumen. Wherea polymeric carrier is provided, the HMG-CoA reductase inhibitor may bephysically bound to the polymer, chemically bound to the polymer, orboth. The coating composition may be a solution that comprises theHMG-CoA reductase inhibitor, the polymer, and a solvent. The solvent maybe removed by, e.g., drying the stent or other methods known in the art.In another embodiment, the coating composition may comprise the HMG-CoAreductase inhibitor and a polymer having a melting point between 30° C.and 50° C., and applying the coating composition to the stent maycomprise melting the coating composition, spraying the melted coating onthe stent, and allowing the coating to solidify. The coating compositionmay include an amount of the HMG-CoA reductase inhibitor that istherapeutically effective for inhibiting regrowth of plaque orinhibiting restenosis. More particularly, the coating composition maycomprise from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,based on the total weight of the coating composition.

In another aspect, the invention can include a method of treatingrestenosis, comprising inserting a coated stent into a body lumen, thecoated stent comprising a stent and a coating composition comprising asubstantially unreacted HMG-CoA reductase inhibitor and a low-melting,nonpolymeric or polymeric carrier, which may be a liquid or a solid. Inone embodiment, the coated stent releases the HMG-CoA reductaseinhibitor in an amount sufficient to inhibit the proliferation of smoothmuscle cells. In another embodiment, the coated stent releases theHMG-CoA reductase inhibitor in an amount sufficient to inhibitrestenosis.

In another aspect, the invention may comprise a method of localizeddelivery of an HMG-CoA reductase inhibitor, comprising inserting acoated stent into a body lumen, the coated stent comprising a stent anda coating composition comprising a substantially unreacted HMG-CoAreductase inhibitor and a low-melting polymeric or nonpolymeric carrier.In one embodiment, the coated stent releases the HMG-CoA reductaseinhibitor in an amount effective to inhibit the proliferation of smoothmuscle cells. In another embodiment, the coated stent releases theHMG-CoA reductase inhibitor in an amount effective to inhibitrestenosis.

In another aspect, the invention can include a coated stent, comprisinga stent and a coating composition comprising a biologically activecomponent and a biodegradable carrier component which may have a meltingpoint of about 50° C. or less, and a catheter which can be coupled tothe coated stent to form a treatment assembly.

In accordance with methods and compositions described herein, restenosismay be prevented or lessened using localized delivery of HMG-CoAreductase inhibitors from a liquid or low-melting carrier coupled to astent placed in a body lumen. Preferably, metal stents are coated with abiocompatible coating composition comprising a carrier and an effectiveamount of an HMG-CoA reductase inhibitor. The coated stent can bedeployed during any conventional percutaneous transluminal coronaryangioplasty (PTCA) procedure. Controlled delivery from a stent of theactive HMG-CoA reductase inhibitor, using a coating such as thatdescribed herein, in an effective amount, can inhibit the regrowth ofplaque and prevent restenosis. While the stents shown and described inthe various embodiments are vascular stents, any type of stent suitablefor deployment in a body lumen of a patient may be used with thecoatings described herein.

EXAMPLES

The following examples are included to demonstrate differentillustrative embodiments or versions of the invention. However, thoseskilled in the art will, in light of the present disclosure, appreciatethat many changes can be made in the specific embodiments which aredisclosed and still obtain a like or similar result without departingfrom the spirit and scope of the invention.

Coronary stents were provided by Baylor Medical School and SulzerIntratherapeutics. Poly(lactic acid)-co-poly(glycolic acid) (PLGA)polymer was purchased from Boehringer Ingelheim. Methylene chloride waspurchased from Aldrich. Poly(ethylene-co-vinyl acetate) (EVA) copolymerwas purchased from Aldrich or Polymer Sciences. Sulzer Carbomedics, Inc.provides medical grade silicone rubber.

Example 1

One hundred (100) mg PCL (poly caprolactone) polymer and 10 mg ofcerivastatin were dissolved in 10 ml methylene chloride solution at roomtemperature. The solution was poured onto a glass plate and the solventwas allowed to evaporate for 12-24 hours. After almost complete removalof the solvent, the cerivastatin-loaded PCL film was removed from theglass plate and was cut to 1.5 cm by 1.5 cm size. The film was mountedon a Palmaz-Schatz coronary endovascular stent. Control PCL films wereprepared in the following manner: 100 mg PCL (poly caprolactone) polymerwas dissolved in 10 ml methylene chloride solution at room temperature.The solution was poured onto a glass plate and the solvent was allowedto evaporate for 12-24 hours. After almost complete removal of thesolvent, the control PCL film was removed from the glass plate and wascut to 1.5 cm by 1.5 cm size. The control film was mounted on aPalmaz-Schatz coronary endovascular stent. Release profiles wereobtained for the coated stents as shown in FIG. 6.

Example 2

100 mg EVA (ethylene-vinyl acetate) polymer and 10 mg of cerivastatinwere dissolved in 10 ml methylene chloride solution at room temperature.The solution was poured onto a glass plate and the solvent was allowedto evaporate for 12-24 hours. After almost complete removal of thesolvent, the cerivastatin-loaded EVA film was removed from the glassplate and was cut to 1.5 cm by 1.5 cm size. The film was mounted on aPalmaz-Schatz coronary endovascular stent. Control EVA films wereprepared in the following manner: 100 mg EVA (ethylene-vinyl acetate)polymer was dissolved in 10 ml methylene chloride solution at roomtemperature. The solution was poured onto a glass plate and the solventwas allowed to evaporate for 12-24 hours. After almost complete removalof the solvent, the control EVA film was removed from the glass plateand was cut to 1.5 cm by 1.5 cm size. The control film was mounted on aPalmaz-Schatz coronary endovascular stent. Release profiles wereobtained for the coated stents as shown in FIG. 5.

Example 3

A 0.6% solution of polycaprolactone dissolved in methylene chloride wasprepared at room temperature. The solution was sprayed onto a SulzerIntratherapeutics nitinol Protege model endovascular stent (6 mm×20 mm)using a semi-automated nebulizer apparatus. The nebulizer spray systemprovided a means of rotating and traversing the length of the stent at acontrolled rate. The traversing component of the apparatus contained aglass nebulizer system that applied nebulized polycaprolactone solutionto the stent at a rate of 3 ml per minute. Once applied, the 10 mgpolymer coating was “reflowed” by application of 60° C. heated air forapproximately 5 seconds. The process of reflowing the polymer providesbetter adherence to the stent surface. A drug-loaded polymer coating canbe provided using this technique by first preparing a 1%-20%cerivastatin/polymer solution in methylene chloride with subsequentapplication to the stent surface using the same nebulizer coatingsystem.

Example 4

A 1% solution of uncured two-part silicone rubber dissolved intrichloroethylene was applied to a “Protege” nitinol stent in the mannerdescribed in Example 3. The coated stent was dried at room temperaturefor 15 minutes to allow the trichloroethylene to evaporate. Once 10 mgof silicone was coated onto the stent, the composite device containingboth uncured polymer and nitinol was heated in a vacuum oven for aperiod of four hours in order to crosslink the silicone coating. Afterthe coated stents were removed from the oven and allowed to cool for aperiod of 1 hour, cerivastatin was loaded into the silicone coating bythe following method. Three mg of cerivastatin was dissolved in 300 μlof methylene chloride at room temperature. A volume of 100 μl ofmethylene chloride was applied to the silicone coating of each stent indropwise fashion. In this manner, each stent was loaded with 1 mgcerivastatin, for a final concentration of 10% w/w. The crosslinkedsilicone absorbed the drug/solvent solution, where the solventsubsequently evaporated at room temperature, leaving behind the drugentrapped within the silicone. By this method, a diffusion-based releasesystem for cerivastatin was created. A release profile was obtained forthe coated stent as shown in FIG. 7.

Example 5

A 10% w/w solution of cerivastatin in vitamin E was created by thefollowing method. Four mg of cerivastatin was dissolved in 100 μl ofmethylene chloride. This solution was added to 36 mg of liquid vitamin Eand mixed manually by stirrer. The solution was allowed to stand at roomtemperature for 1 hour to enable the methylene chloride to evaporatefrom the solution. The resulting cerivastatin/vitamin E mixture was usedto coat three Protg model stents by simple surface application.Approximately 10-12 mg of vitamin E and drug was deposited on eachstent. A release profile was obtained for the coated stent as shown inFIG. 8.

Example 6

A 50 ml round bottom flask with a Teflon coated magnetic stirrer isflame dried under repeated cycles of vacuum and dry nitrogen. Two (2) gtrimethylol propane, 11.68 g D,L-lactide, and 0.20 mg stannous octoateare charged to the flask. The flask is then heated to 165° C. for 16hours and then cooled. The liquid product is dissolved in 30 ml tolueneand precipitated in large excess cold hexane. The precipitated polymer,which is a liquid at room temperature, is isolated and can be used incoating stents.

Example 7

Polycaprolactone diol (MW 2000) (PCL 2000) is purchased from Aldrich.This polymer melts at approximately 60-70° C., depending upon itsthermal (cooling) history and the degree of crystallinity in the bulkpolymer. This polymer is insoluble in water.

Example 8

Polycaprolactone triol (MW 300) (PCL 300) is purchased from Aldrich andused as received. This polymer is liquid at room temperature and isimmiscible with water.

Example 9

One (1) g of PCL 300, a liquid at room temperature, and 50 mg of PCL2000, a solid at room temperature, are mixed to obtain a viscous mixturewhich is liquid at room temperature. The viscosity of the mixture isgreater than the viscosity of PCL 300.

Example 10

One (1) g PCL 300 (See Example 6) and 10 mg rifampin are added to a 2 mlglass vial. A 7×20 mm metal stent (Lot R0036203, Sulzer IntraTherapeutics) is added to the vial. The excess liquid on the surface ofthe stent is removed. The coated stent is then sterilized using ethyleneoxide, compressed, and mounted on a balloon angioplasty catheter. It isthen deployed at a diseased site in an artery using standard balloonangioplasty techniques and implanted at the site of reduced blood flowor obstruction of the artery. The hydrophobic liquid layer on the stentreleases the drug in a controlled fashion.

Example 11

One (1) g PCL 300 (see Example 6) and 10 mg rifampin are added to a 2 mlglass vial. A paint brush is used to coat an angioplasty balloon surfacewith the PCL 300-rifampin mixture. The balloon is sterilized usingethylene oxide, compressed, and mounted on the balloon angioplastycatheter. It is then deployed at a diseased site in a coronary arteryusing standard balloon angioplasty technique. The coated balloon isexpanded at the site of reduced blood flow or obstruction in the artery.The contact of the balloon surface with the arterial lumen walltransfers a portion of the liquid coating onto the wall surface as wellas onto the material obstructing the arterial lumen. The hydrophobicliquid layer is transferred onto the lumen walls and onto theobstructing material, delivering the bioactive compound in a controlledmanner.

In preferred embodiments, the controlled release studies were done todetermine the integrity and activity of cerivastatin released fromstents coated with polymer and cerivastatin. Stents coated according tothe process of Example 2 were immersed in an Eppendorf tube containing 1ml phosphate buffered saline (PBS) and incubated on a rotator in a 37°C. oven. Buffer exchanges were performed at 1, 2, and 4 days followingimmersion in PBS. Collected samples were assayed for the spectralcharacteristics of cerivastatin using a UV-VIS spectrophotometer.Cerivastatin released from an EVA and cerivastatin coated stent such asthe stent of Example 2 and pure cerivastatin in deionized water hadalmost identical UV-VIS spectra, as shown in FIG. 4, suggesting that thecerivastatin released from the stent was unaltered and thus remainedbiologically active.

The release of cerivastatin from stents coated according to the processof Example 2 was monitored over 7 days, as shown in FIG. 5. An EVA andcerivastatin coated stent such as the stent of Example 2 released >20μg/ml cerivastatin per day, which is significantly higher than the 0.5.mu.g/ml concentration needed to inhibit proliferation of smooth musclecells. Thus, stents produced according to this invention release asufficient amount of cerivastatin to inhibit the proliferation of smoothmuscle cells which occurs during restenosis.

The release of cerivastatin from stents coated with polycaprolactonefilm according to the process of Example 1 was monitored over 80 days,as shown in FIG. 6. A polycaprolactone and cerivastatin coated stentsuch as the stent of Example 1 released >20 μg/ml cerivastatin per day.The release of cerivastatin from stents according to the process ofExample 4 was monitored over 20 days, as shown in FIG. 7. A cerivastatinand silicone coated stent such as the stent of Example 4 released >20μg/ml cerivastatin per day.

The release of cerivastatin from stents according to the process ofExample 5 was monitored over 11 days, as shown in FIG. 8. A liquidvitamin E and cerivastatin coated stent such as the stents of Example 5released >20 μg/ml cerivastatin per day.

While the foregoing is directed to embodiments of the present invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow, including equivalents.

What is claimed is:
 1. A method of coating a stent comprising: providinga stent; providing a coating composition comprising an HMG-CoA reductaseinhibitor in an amount of about 1 to 50 wt. %, and a polymericbiodegradable carrier component comprising a polymer selected frompolycaprolactone, ethylene-vinyl acetate polymer, and a two-partsilicone rubber; expanding the stent to an increased diameter; andapplying the coating composition to the stent, wherein the HMG-CoAreductase inhibitor is released from the stent at a rate of >20 μg/mlper day.
 2. The method of claim 1, wherein applying the coatingcomposition comprises spraying or painting the coating composition ontothe stent, or immersing the stent in the coating composition.
 3. Themethod of claim 1, wherein the HMG-CoA reductase inhibitor is selectedfrom cerivastatin, atorvastatin, simvastatin, fluvastatin, lovastatin,and pravastatin.
 4. The method of claim 1, wherein the HMG-CoA reductaseinhibitor comprises cerivastatin.
 5. The method of claim 1, wherein thecoating composition further comprises one or more bioactive compoundsselected from the group consisting of paclitaxel, paclitaxel analogs,actinomycin D, actinomycin D analogs, rapamycin, rapamycin analogs, andmixtures thereof.
 6. A method of coating a stent comprising: providing astent; providing a first coating composition comprising a first carrierand an HMG-CoA reductase inhibitor in an amount from about 1 to 50 wt. %of the first coating composition; expanding the stent to an increaseddiameter; applying the first coating composition to the stent; dryingthe stent after the first coating composition is applied to the stent;and applying a second coating composition comprising a polymericbiodegradable carrier to the dried stent.
 7. The method of claim 6,wherein providing the first coating composition comprises mixing theHMG-CoA reductase inhibitor, the first carrier, and a solvent underconditions such that the HMG-CoA reductase inhibitor does not chemicallyreact to any substantial degree with the first carrier.
 8. The method ofclaim 6, wherein the first carrier comprises a nonpolymeric carrier. 9.The method of claim 8, wherein the first carrier is a liquid at bodytemperature.
 10. The method of claim 8, wherein the first carrier is asolid at room temperature.
 11. The method of claim 8, wherein thenonpolymeric carrier is selected from the group consisting of Vitamin E,Vitamin E acetate, Vitamin E succinate, oleic acid, peanut oil andcottonseed oil.
 12. The method of claim 6, wherein the HMG-CoA reductaseinhibitor is selected from the group consisting of cerivastatin,atorvastatin, simvastatin, fluvastatin, lovastatin, and pravastatin. 13.The method of claim 6, wherein applying the first coating compositioncomprises spraying or painting the first coating composition onto thestent, or immersing the stent in the first coating composition.
 14. Themethod of claim 6, wherein providing the first coating compositioncomprises forming the first coating composition into a film, andapplying the first coating comprises wrapping the film around the stent.15. The method of claim 6, wherein the polymeric biodegradable carriercomprises a polymer selected from polycaprolactone, ethylene-vinylacetate polymer, and a two-part silicone rubber.
 16. The method of claim6, wherein the second coating composition further comprises asubstantially unreacted HMG-CoA reductase inhibitor.
 17. The method ofclaim 6, wherein the stent further comprises one or more bioactivecompounds selected from the group consisting of paclitaxel, paclitaxelanalogs, actinomycin D, actinomycin D analogs, rapamycin, rapamycinanalogs, and mixtures thereof.
 18. The method of claim 6, wherein theHMG-CoA reductase inhibitor is released from the stent at a rate of >20μg/ml per day.